The present invention relates to a novel process for the preparation of chiral selective glucocorticoid receptor agents.
The glucocorticoid receptor (GR) has an essential role in regulating human physiology and immune response. Steroids which interact with GR have been shown to be potent antiinflammatory agents. Steroidal GR ligands, however, have side effects associated with chronic dosing believed to be the result of cross-reactivity with other steroid receptors such as estrogen, progesterone, androgen, and mineralocorticoid receptors which have somewhat homologous ligand binding domains. Therefore, nonsteroidal agents selective for GR are actively being researched for the treatment of inflammation, inflamatory disease, immune and autoimmune diseases.
The present invention is directed to a process for preparing biaryl atropisomers that are used to prepare chiral GR agents. The process proceeds through a chirality transfer from a stereogenic center of a secondary alcohol to the biaryl stereogenic axis via regioselective intramolecular migration. This methodology allows for the preparation of a single biaryl atropisomer in high yield with high diastereoselectivity which subsequently leads to the synthesis of chiral glucocorticoid receptor agents.
In particular, the process is used to prepare chiral 5-substituted-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolines wherein (5S)-5-allyl-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline is a preferred chiral GR agent.
The present invention is directed to a process for the preparation of biaryl atropisomers that can be used for preparation of compounds of formula (I) 
wherein
R1 is selected from alkenyl, alkyl, alkynyl and aryl, wherein alkenyl is preferred and wherein allyl is most preferred;
R2, R3 and R4 are each independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkynyl, aryl and halogen; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached, together form a ring wherein the ring is selected from aryl, cycloalkyl and heterocycle, wherein hydrogen is preferred for each of R2, R3 and R4;
R5 is selected from hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxycarbonyloxy, alkoxysulfonyloxy, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, alkynyl, alkynyloxy, aryl, arylalkoxy, arylalkoxycarbonyloxy, aryloxy, arylsulfonyloxy, haloalkoxy, haloalkylcarbonyloxy, haloalkylsulfonyloxy, halogen, heterocycle and (NRCRD)carbonyloxy, wherein alkoxy and haloalkylsulfonyl are preferred and wherein methoxy and trifluoromethanesulfonate are most preferred;
RC and RD are each independently selected from hydrogen and alkyl;
R6, R7, R8 and R9 are each independently selected from hydrogen, alkoxy, alkenyl, alkyl, alkynyl, aryl and halogen; or
R6 and R7 or R7 and R8 or R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring is selected from aryl, cycloalkyl and heterocycle, wherein hydrogen is preferred for each of R6 and R7; R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring is a heterocycle is preferred and wherein R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring 4,6,6-trimethyl-1,2,3,6-tetrahydropyridinyl is most preferred;
wherein the process comprises the steps of:
(a) treating a compound of formula (Ia) 
xe2x80x83with a base in a first solvent wherein RA is a hydroxy protecting group;
(b) treating the product of step (a) with an electrophile to provide a compound of formula (Ib); 
xe2x80x83wherein RB is selected from alkoxycarbonyl, alkoxysulfonyl, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkyl, arylsulfonyl, haloalkyl, haloalkylcarbonyl, haloalkylsulfonyl and (NRCRD)carbonyl, wherein alkyl and haloalkylsulfonyl are preferred and methyl and trifluoromethylsulfonyl are most preferred; RC and RD are each independently selected from hydrogen and alkyl;
(c) treating the compound of formula (Ib) with a hydroxy deprotecting reagent in a second solvent to provide a compound of formula (Ic); and 
(d) treating the compound of formula (Ic) with an azo reagent and a phosphine reagent in a third solvent to provide the compound of formula (I).
According to another embodiment, the present invention further comprises the steps of the process described above wherein step (a) is conducted from about xe2x88x925xc2x0 C. to about 25xc2x0 C.; isolating the product of step (b) by pouring step (b) into saturated ammonium chloride solution; stirring the solution; separating the aqueous phase from the organic phase; washing the organic phase with brine; drying the organic phase over sodium sulfate; concentrating the organic phase to provide an oil; dissolving the oil in heptane; extracting the heptane with acetonitrile; treating the heptane with charcoal; and concentrating the heptane to provide a compound of formula (Ib); step (c) is conducted between 18xc2x0 C. and about 25xc2x0 C. for about 12 to 36 hours; isolating the product of step (c) by pouring step (c) into a saturated solution of ammonium chloride; stirring the solution; adding tert-butyl methyl ether to the solution; stirring the solution for about 5 to 20 minutes; separating the aqueous phase from the organic phase; washing the organic phase with brine; drying the organic phase over sodium sulfate; concentrating the organic phase to provide a solid; suspending the solid in isopropanol:heptane 1:12.5 for 1 to 3 hours; cooling the isopropanol:heptane 1:12.5 to xe2x88x925xc2x0 C. to about 5xc2x0 C.; and filtering the isopropanol:heptane 1:12.5 to provide a compound of formula (Ic); in step (d) the product of step (c) and the triphenylphosphine are dissolved in the tetrahydrofuran at a temperature between 18xc2x0 C. and about 25xc2x0 C.; the tetrahydrofuran may optionally be cooled to about xe2x88x925xc2x0 C. to about 15xc2x0 C.; and the diisobutyl azodicarboxylate is added to the tetrahydrofuran over about 0.25 to 3 hours while maintaining the temperature of the tetrahydrofuran from xe2x88x925xc2x0 C. to about 25xc2x0 C.; isolating the product from step(d) by concentrating the tetrahydrofuran to about xc2xc to ⅓ of original volume; adding heptane to the tetrahydrofuran; cooling the tetrahydrofuran/heptane mixture to about xe2x88x925xc2x0 C. to about 5xc2x0 C.; allowing the tetrahydrofuran/heptane mixture to stand for 12 to 24 hours; filtering the tetrahydrofuran/heptane mixture; repeating concentration, cooling and filtering until small amount of solid precipitates out of the tetrahydrofuran/heptane mixture; concentrating the tetrahydrofuran/heptane mixture to provide crude product of step (d); purifying the crude product of step (d) by flash chromatography to provide the product of step (d); and recrystallizing the product of step (d) from isopropanol.
The process of the present invention is particularly useful for preparing (5S)-5-allyl-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline and (5S)-5-allyl-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-10-yl trifluoromethanesulfonate.
According to yet another embodiment, the present invention discloses a process for the preparation of a compound having formula (II) 
wherein
R1 is selected from selected from the group consisting of alkenyl, alkyl, alkynyl and aryl;
R2, R3 and R4 are each independently selected from the group consisting of hydrogen, alkoxy, alkenyl, alkyl, alkynyl and halogen; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached, together form a ring wherein the ring is selected from the group consisting of aryl, cycloalkyl and heterocycle;
R5 is selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxycarbonyloxy, alkoxysulfonyloxy, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, alkynyl, alkynyloxy, aryl, arylalkoxy, arylalkoxycarbonyloxy, arylsulfonyloxy, haloalkoxy, haloalkylcarbonyloxy, haloalkylsulfonyloxy, halogen, heterocycle and (NRCRD)carbonyloxy; and
R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, alkoxy, alkenyl, alkyl, alkynyl and halogen; or
R6 and R7 or R7 and R8 or R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring is selected from the group consisting of aryl, cycloalkyl and heterocycle;
wherein said process comprises the steps of:
(a) treating a compound of formula (IIa) 
xe2x80x83with a base in a first solvent, wherein RA is a hydroxy protecting group and R1, R2, R3, R4, R6, R7, R8 and R9 are as defined above
(b) treating the product of step (a) with an electrophile to provide a compound of formula (IIb) 
xe2x80x83wherein RB is selected from the group consisting of alkoxycarbonyl, alkoxysulfonyl, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkyl, arylsulfonyl, haloalkyl, haloalkylcarbonyl, haloalkylsulfonyl and (NRCRD)carbonyl wherein RC and RD are selected from the group consisting of hydrogen and alkyl; and RA, R1, R2, R3, R4, R6, R7, R8 and R9 are as defined above;
(c) treating the compound of formula (IIb) with a hydroxy deprotecting reagent in a second solvent to provide a compound of formula (IIc) 
xe2x80x83wherein RB, R1, R2, R3, R4, R6, R7, R8 and R9 are as defined above; and
(d) treating the compound of formula (IIc) with an azo reagent and a phosphine reagent in a third solvent to provide the compound of formula (II).
According to a further embodiment, the present invention discloses a process for the preparation of a compound having formula (I) 
wherein
R1 is selected from the group consisting of alkenyl, alkyl, alkynyl and aryl, wherein alkenyl is preferred and wherein allyl is most preferred;
R2, R3 and R4 are each independently selected from the group consisting of hydrogen, alkoxy, alkenyl, alkyl, alkynyl, aryl and halogen; or
R2 and R3 or R3 and R4 together with the carbon atoms to which they are attached, together form a ring wherein the ring is selected from the group consisting of aryl, cycloalkyl and heterocycle, wherein hydrogen is preferred for each of R2, R3 and R4; 
R5 is selected from the group consisting of hydrogen, alkenyl, alkenyloxy, alkoxy, alkoxycarbonyloxy, alkoxysulfonyloxy, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, alkynyl, alkynyloxy, aryl, arylalkoxy, arylalkoxycarbonyloxy, aryloxy, arylsulfonyloxy, haloalkoxy, haloalkylcarbonyloxy, haloalkylsulfonyloxy, halogen, heterocycle and (NRCRD)carbonyloxy, wherein alkoxy is preferred and methoxy is most preferred;
RC and RD are each independently selected from hydrogen and alkyl; and
R6, R7, R8 and R9 are each independently selected from the group consisting of hydrogen, alkoxy, alkenyl, alkyl, alkynyl, aryl and halogen; or
R6 and R7 or R7 and R8 or R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring is selected from the group consisting of aryl, cycloalkyl and heterocycle, wherein hydrogen is preferred for each of R6 and R7; R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring is a heterocycle is preferred, wherein R8 and R9 together with the carbon atoms to which they are attached, together form a ring wherein the ring 4,6,6-trimethyl-1,2,3,6-tetrahydropyridinyl is most preferred;
wherein said process comprises the steps of:
(a) treating a compound of formula (Ia) 
xe2x80x83with at least two molar equivalents of a hydroxy deprotecting reagent in a first solvent, wherein RA is a hydroxy protecting group and R1, R2, R3, R4, R6, R7, R8 and R9 are as defined above, to provide a compound of formula (Ia) wherein RA is hydrogen;
(b) treating the product of step (a) with an azo reagent and a phosphine reagent in a second solvent, a preferred second solvent is tetrahydrofuran.
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term xe2x80x9csingle biaryl atropisomerxe2x80x9d as used herein, refers to a biaryl atropisomer of general formula (Ib) or (IIb) shown below: 
xe2x80x83wherein R1, R2, R3, R4, R6, R7, R8 and R9 are as defined in formula (I) for a biaryl atropisomer of general formula (Ib); R1, R2, R3, R4, R6, R7, R8 and R9 are as defined in formula (II) for a biaryl atropisomer of general formula (IIb); RA is a hydroxy protecting group and RB is selected from alkoxycarbonyl, alkoxysulfonyl, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkyl, arylsulfonyl, haloalkyl, haloalkylcarbonyl, haloalkylsulfonyl and (NRCRD)carbonyl.
The term xe2x80x9cazo reagentxe2x80x9d as used herein, refers to a reagent, Rxe2x80x94Nxe2x95x90Nxe2x80x94R, wherein R is selected from alkoxycarbonyl and cycloalkyloxycarbonyl. Representative examples of azo reagent include, but are not limited to, diethyl azodicarboxylate, di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, dimethyl azodicarboxylate and dicyclohexyl azodicarboxylate. A preferred azo reagent is selected from diethyl azodicarboxylate, di-tert-butyl azodicarboxylate and diisopropyl azodicarboxylate. A most preferred azo reagent is diisopropyl azodicarboxylate.
The term xe2x80x9cbasexe2x80x9d as used herein, refers to any molecular moiety that can remove the hydrogen from a secondary alcohol. Representative examples of base include, but are not limited to, alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and potassium tert-butoxide; hydrides such as sodium hydride, potassium hydride and lithium hydride; amides such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide. A preferred base is potassium tert-butoxide.
The term xe2x80x9celectrophilexe2x80x9d as used herein, refers to any molecular moiety that contains a carbon atom or a sulfur atom wherein the carbon or sulfur atom can accept a pair of electrons. Representative examples of electrophile include, but are not limited to, methyltriflate, methyltosylate, dimethylsulfate and trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide; acid chlorides such as acetyl chloride, propionyl chloride, trimethylacetyl chloride and dimethylcarbamyl chloride; alkenyl halides such as allyl bromide; alkyl halides such as iodomethane, iodoethane, trifluoromethyl iodide, perfluoroethyl iodide, benzyl bromide and benzyl chloride; alkynyl halides such as propargyl bromide; anhydrides such as acetic anhydride, trifluoromethyl anhydride and di-tert-butyl dicarbonate; chloroformates such as benzyl chloroformate, ethyl chloroformate and isopropyl chloroformate; sulfonyl chlorides such as methanesulfonyl chloride (mesyl chloride), para-toluenesulfonyl chloride (tosyl chloride) and phenylsulfonyl chloride; and sulfonic anhydrides such as trifluoromethanesulfonic anhydride (triflic anhydride). A preferred electrophile is selected from trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide and iodomethane.
The term xe2x80x9chydroxy protecting groupxe2x80x9d as used herein, refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures. Preferred hydroxy protecting groups of the present invention include, but are not limited to, alkylcarbonyl, (alkyl)(diaryl)silyl, (trialkyl)silyl, (triaryl)silyl and (triarylalkyl)silyl. Representative examples of hydroxy protecting groups include, but are not limited to, acetyl, ethylcarbonyl, propylcarbonyl, tert-butylcarbonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl and triphenylsilyl. A preferred hydroxy protecting group is tert-butyldimethylsilyl.
The term xe2x80x9chydroxy deprotecting reagentxe2x80x9d as used herein, refers to a reagent that removes a hydroxy protecting group. Representative examples of hydroxy deprotecting reagents includes, but is not limited to, a source of fluoride anion such as tetrabutylammonium fluoride, potassium fluoride and hydrogen fluoride; inorganic acids such as hydrochloric acid and hydrobromic acid; organic acids such as acetic acid and trifluoroacetic acid; a source of aqueous hydroxide ion such as aqueous potassium hydroxide, aqueous sodium hydroxide, aqueous potassium carbonate and aqueous sodium bicarbonate. A preferred hydroxy deprotecting reagent is tetrabutylammonium fluoride.
The term xe2x80x9cphosphine reagentxe2x80x9d as used herein refers to (RE)3P wherein RE is selected from alkyl and aryl. Representative example of (RE)3P include, but are not limited to, tributylphosphine, tri-tert-butylphosphine, triisobutylphosphine, triisopropylphosphine, tripropylphosphine, triethylphosphine, trimethylphosphine, tris(4-methylphenyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(4-chlorophenyl)phosphine, tris(4-bromophenyl)phosphine and triphenylphosphine. A preferred phosphine reagent is triphenylphosphine.
The term xe2x80x9cfirst solventxe2x80x9d as used herein, refers to any organic solvent that will allow the reaction in step (a) and the reaction in step (b) to proceed to completion or substantially to completion. A preferred first solvent is tetrahydrofuran.
The term xe2x80x9csecond solventxe2x80x9d as used herein, refers to any organic solvent that will allow the reaction in step (c) to proceed to completion or substantially to completion. A preferred second solvent is tetrahydrofuran.
The term xe2x80x9cthird solventxe2x80x9d as used herein, refers to any organic solvent that will allow the reaction in step (d) to proceed to completion or substantially to completion. A preferred third solvent is tetrahydrofuran.
The term xe2x80x9calkenylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkenyloxy include, but are not limited to, allyloxy, 2-butenyloxy and 3-butenyloxy.
The term xe2x80x9calkoxyxe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term xe2x80x9calkoxycarbonyloxyxe2x80x9d as used herein, refers to an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxycarbonyloxy include, but are not limited to, methoxycarbonyloxy, ethoxycarbonyloxy, and tert-butoxycarbonyloxy.
The term xe2x80x9calkoxysulfonylxe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
The term xe2x80x9calkoxysulfonyloxyxe2x80x9d as used herein, refers to an alkoxysulfonyl group, as defined herein, appended appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxysulfonyloxy include, but are not limited to, methoxysulfonyloxy, ethoxysulfonyloxy and propoxysulfonyloxy.
The term xe2x80x9calkylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term xe2x80x9calkylcarbonylxe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term xe2x80x9calkylcarbonyloxyxe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, propionyloxy and (2,2-dimethylpropanoyl)oxy.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
The term xe2x80x9calkylsulfonyloxyxe2x80x9d as used herein, refers to an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkylsulfonyloxy include, but are not limited to, methylsulfonyloxy and ethylsulfonyloxy.
The term xe2x80x9calkynylxe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term xe2x80x9calkynyloxyxe2x80x9d as used herein, refers to an alkynyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkynyloxy include, but are not limited to, 2-propynyloxy and 2-butynyloxy.
The term xe2x80x9carylxe2x80x9d as used herein, refers to a phenyl group. The aryl groups of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, nitro, xe2x80x94NRCRD and (NRCRD)carbonyl.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, benzyloxy, 2-phenylethoxy and 5-phenylpentyloxy.
The term xe2x80x9carylalkoxycarbonylxe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl.
The term xe2x80x9carylalkoxycarbonyloxyxe2x80x9d as used herein, refers to an arylalkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of arylalkoxycarbonyloxy include, but are not limited to, benzyloxycarbonyloxy.
The term xe2x80x9carylalkylxe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl and 2-phenylethyl.
The term xe2x80x9caryloxyxe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of aryloxy include, but are not limited to, phenoxy, 4-chlorophenoxy and 3,4-dimethylphenoxy.
The term xe2x80x9carylsulfonylxe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl and 4-methylphenylsulfonyl.
The term xe2x80x9carylsulfonyloxyxe2x80x9d as used herein, refers to an arylsulfonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of arylsulfonyloxy include, but are not limited to, phenylsulfonyloxy and 4-methylphenylsulfonyloxy.
The term xe2x80x9ccarbonylxe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccyanoxe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein, refers to a saturated cyclic hydrocarbon group containing from 4 to 6 carbons. Examples of cycloalkyl include cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9ccycloalkyloxyxe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of cycloalkyloxy include, but are not limited to, cyclobutyloxy, and cyclohexyloxy.
The term xe2x80x9ccycloalkyloxycarbonylxe2x80x9d as used herein, refers to cycloalkyloxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkyloxycarbonyl include, but are not limited to, cyclohexyloxycarbonyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
The term xe2x80x9chaloalkylxe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl and pentafluoroethyl.
The term xe2x80x9chaloalkylcarbonylxe2x80x9d as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of haloalkylcarbonyl include, but are not limited to, trifluoromethylcarbonyl.
The term xe2x80x9chaloalkylcarbonyloxyxe2x80x9d as used herein, refers to a haloalkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkylcarbonyloxy include, but are not limited to, trifluoromethylcarbonyloxy.
The term xe2x80x9chaloalkylsulfonylxe2x80x9d as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of haloalkylsulfonyl include, but are not limited to, trifluoromethylsulfonyl and pentafluoroethylsulfonyl.
The term xe2x80x9chaloalkylsulfonyloxyxe2x80x9d as used herein, refers to a haloalkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of haloalkylsulfonyloxy include, but are not limited to, trifluoromethylsulfonyloxy and pentafluoroethylsulfonyloxy.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d as used herein, refers to a monocyclic or bicyclic ring system. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has from 0-2 double bonds and the 6- and 7-membered ring have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, triazinyl, triazolyl, and trithianyl. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazolyl, benzodioxinyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, cinnolinyl, indazolyl, indolyl, 2,3-dihydroindolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, phthalazinyl, pyranopyridinyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and thiopyranopyridinyl.
The heterocycles of this invention can be substituted with 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, nitro, oxo, xe2x80x94NRCRD and (NRCRD)carbonyl. Representative examples of substituted heterocycles includes, but is not limited to, 4,6,6-trimethyl-1,2,3,6-tetrahydropyridinyl.
The term xe2x80x9cnitroxe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9cxe2x80x94NRCRDxe2x80x9d as used herein, refers to two groups, RC and RD, which are appended to the parent molecular moiety through a nitrogen atom. RC and RD are each independently selected from hydrogen and alkyl. Representative examples of xe2x80x94NRCRD include, but are not limited to, amino, methylamino, dimethylamino, ethylmethylamino and diethylamino.
The term xe2x80x9c(NRCRD)carbonylxe2x80x9d as used herein, refers to a xe2x80x94NRCRD group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of (NRCRD)carbonyl include, but are not limited to, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, (ethylmethylamino)carbonyl, and (diethylamino)carbonyl.
The term xe2x80x9c(NRCRD)carbonyloxyxe2x80x9d as used herein, refers to a (NRCRD)carbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of (NRCRD)carbonyloxy include, but are not limited to, aminocarbonyloxy, (methylamino)carbonyloxy, (dimethylamino)carbonyloxy, (ethylmethylamino)carbonyloxy and (diethylamino)carbonyloxy.
The term xe2x80x9coxoxe2x80x9d as used herein, refers to a xe2x95x90O moiety.
The term xe2x80x9csulfonylxe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9c(alkyl)(diaryl)silylxe2x80x9d as used herein, refers to an alkyl group, as defined herein, and two aryl groups, as defined herein, appended to the parent molecular moiety through a silane atom. Representative examples of (alkyl)(diaryl)silyl, include, but are not limited to, methyldiphenylsilyl and tert-butyldiphenylsilyl.
The term xe2x80x9c(trialkyl)silylxe2x80x9d as used herein, refers to three independent alkyl groups, as defined herein, appended to the parent molecular moiety through a silane atom. Representative examples of (trialkyl)silyl, include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl and tert-butyldimethylsilyl.
The term xe2x80x9c(triaryl)silylxe2x80x9d as used herein, refers to three independent aryl groups, as defined herein, appended to the parent molecular moiety through a silane atom. Representative examples of (triaryl)silyl, include, but are not limited to, triphenylsilyl.
The term xe2x80x9c(triarylalkyl)silylxe2x80x9d as used herein, refers to three independent arylalkyl groups, as defined herein, appended to the parent molecular moiety through a silane atom. Representative examples of (triarylalkyl)silyl, include, but are not limited to, tribenzylsilyl.
Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: t-Bu for tert-butyl; DIAD for diisopropyl azodicarboxylate; DMSO for dimethylsulfoxide, DIBAL or DIBAL-H for diisobutylaluminum hydride; EtOAc for ethyl acetate; HPLC for high pressure liquid chromatography; IPA for isopropyl alcohol; Ipc for isopinocamphenyl; MTBE for tert-butyl methyl ether; TBAF for tetrabutylammonium fluoride; TBS for tert-butyldimethylsilyl; TBSCl for tert-butyldimethylsilyl chloride; THF for tetrahydrofuran; Tf for xe2x80x94S(O)2CF3; TLC for thin layer chromatography; and TMS for trimethylsilyl.
The present invention will be better understood in connection with the following synthetic Schemes. 
Scheme 1 describes the general applicability of the present invention to preparing compounds of general formula (I). Compounds of general formula (Ia), wherein base, electrophile, RB, R1, R2, R3, R4, R6, R7, R8 and R9 are as defined herein and RA is a hydroxy protecting group, as defined herein, wherein a preferred hydroxy protecting group is tert-butyldimethylsilyl, can be treated with a base that is sufficiently basic enough to remove a proton from a secondary alcohol, a preferred base is potassium tert-butoxide, in a solvent such as tetrahydrofuran to provide an intermediate phenolic anion. The base removes the proton from the secondary alcohol facilitating migration of the hydroxy protecting group, RA, spacially nearest to the alkoxide resulting in the generation of a phenolic anion which can be treated with any electrophile, as defined herein, to provide an atropisomer of general formula (Ib). The two protecting groups, RA, can then be removed under standard conditions depending on RA to provide compounds of general formula (Ic). The phenolic oxygen, in compounds of general formula (Ic), is spacially orientated for nucleophilic backside attack on the carbon atom attached to the hydroxy group. This spacial arrangement in the presence of an azo and a phosphine reagent, as defined herein, in a solvent such as tetrahydrofuran facilitates an intramolecular displacement reaction providing compounds of general formula (I).
As would be understood by one skilled in the art, the opposite enantiomer of compounds of general formula (Ia) will provide the opposite enantiomer of compounds of formula (I). 
Compounds of general formula (7), wherein RB, R1, R2, R3, R4, R6 and R7 are as defined in formula (I), can be prepared as described in Scheme 2. 1,2-Dihydro-5H-chromeno[3,4-f]quinolin-5-ones of general formula (1), prepared as described in International Publication Number WO 99/41256 and which is incorporated by reference herein, can be treated with a base such as potassium tert-butoxide and a hydroxy protecting reagent such as tert-butyldimethylsilyl chloride to provide lactones of general formula (2). Lactones of general formula (2) can be treated with a reducing agent such as diisobutylaluminum hydride in toluene at xe2x88x9278xc2x0 C. to provide lactols of general formula (3). Lactols of general formula (3) can be treated with a base such as potassium tert-butoxide and then treated with any electrophile such as tert-butyldimethylsilyl chloride to provide bis(silyl) aldehydes of general formula (4). Bis(silyl) aldehydes of general formula (4) can be treated with a chiral chelating agent such as (xe2x88x92) (Ipc)2BCl and a compound of general formula (5) wherein X is MgBr, Li or TMS in a solvent such as tert-butyl methyl ether to provide chiral alcohols of general formula (6). Chiral alcohols of general formula (6) can be processed as described in Scheme 1 or the Examples contained herein to provide compounds of general formula (7).
As would be understood by one skilled in the art, treating bis(silyl) aldehydes of general formula (4) with (+) (Ipc)2BCl and a compound of general formula (5) will provide the opposite enantiomer of compounds of general formula (6) and processing the opposite enantiomer of compounds of general formula (6) as described in Scheme 1 will provide the opposite enantiomer of compounds of general formula (7). 
Compounds of general formula (12), wherein R1, R2, R3, R4, R6, R7, R8 and R9 are as defined in formula (I) and R5 is selected from alkenyl, alkyl, alkynyl, aryl and heterocycle, can be prepared as described in Scheme 3. Compounds of general formula (Ia) can be treated with a base and then an electrophile wherein the electrophile is trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide or trifluoromethanesulfonic anhydride as described in Scheme 1 or the Examples contained herein to provide triflates of general formula (10). Triflates of general formula (10) can be treated under Heck, Suzuki or Stille conditions, which are well known to those of skill in the art, to provide compounds of general formula (11). Compounds of general formula (11) can be processed as described Scheme 1 or the Examples contained herein to provide compounds of general formula (12). 
Alternatively, Compounds of general formula (I), wherein electrophile, RA, R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined herein, can be prepared as described in Scheme 4. Compounds of general formula (Ia) can be treated with a hydroxy deprotecting reagent such as tetrabutylammonium fluoride, when RA is selected from (alkyl)(diaryl)silyl, (trialkyl)silyl, (triaryl)silyl or (triarylalkyl)silyl wherein tert-butyldimethylsilyl preferred, to provide triols of general formula (14). Triols of general formula (14) can be treated under Mitsunobu conditions as described in Scheme 1 to provide compounds of general formula (15). Compounds of general formula (15) can be processed as described in Schemes 1-3 to provide compounds of general formula (I).
The present invention is now described by the following Examples in connection with particularly preferred embodiments of Schemes 1-4. The following Examples are not intended to limit the scope the present invention. The present invention covers all alternatives, modifications and equivalents included in the appended claims. Thus, the following Examples illustrate a preferred practice of the invention, it being understood that the Examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.